The purpose of this application is to delve into amino acid problems to which poor or less effective methodologies exist. This proposal describes plans to further develop the utility of the glycine templates developed in our laboratory for the asymmetric synthesis of complex, densely functionalized amino acids and derivatives in optically pure form. The specific targets that have been selected for the upcoming grant cycle have been chosen by the following criteria: (1) the synthetic targets all contain beta-substitution (in some cases, beta,gamma-polysubstitution) in the amino acid side chain; (2) the synthetic targets are biomedically interesting and important; and (3) methodologies to access these types of substances are, in general, lacking in the literature. During the coming grant period, plans are described to develop new synthetic methodologies necessary to achieve the asymmetric total synthesis of the following natural products: (1) nitrone dipolar cycloaddition reactions as applied to the asymmetric total synthesis of cylindrospermopsin; (2) development of novel intramolecular azomethine ylid dipolar cycloaddition reactions for application to the asymmetric total synthesis of palau'amine; (3) diastereoselective aldol and lactone functionalization methods for application to a short, asymmetric total synthesis of quinine featuring a facially selective intramolecular SN2' cyclization reaction; (4) utilization of novel diastereoselective azomethine ylide dipolar cycloaddition strategies for a concise, asymmetric total synthesis of nakadomarin A and the manzamine alkaloids; (5) manipulation of a facially selective intramolecular SN2' cyclization reaction for the asymmetric total synthesis of spiroquinazoline and alantrypinone. A shorter-term goal will be devoted to completion of the asymmetric total synthesis of the proteasome inhibitors TMC-95A/B and synthetic analogs. In each area (except the quinine project), biological studies of synthetic analogs of the biologically active natural products will be undertaken. [unreadable] [unreadable]